Molecular Design,Synthesis And Anti-HIV Activity Research Of 2-thiomethylpyrimidine Derivatives(?)

AIDs,also known as Acquired Immunodeficiency Syndrome,is a kind of disease caused by human immunodeficiency virus(HIV)infection that causes systemic immune function loss.Since the first discovery of AIDS in the United States in June 1981,AIDS has become one of the ten most deadly diseases that pose a serious threat to humanity.From the beginning of anti-HIV-1 drug development to the present,non-nucleoside reverse transcriptase inhibitors have been a research hotspot for the development of anti-HIV-1 virus.Dihydroalkoxybenzyloxopyrimidines(DABOs)derivatives are a representative class of non-nucleoside reverse transcriptase inhibitors(NNRTIs).The toxic side effects and high anti-HIV-1 activity have received much attention.Based on the structure-activity relationship of S-DABO NNRTIs,this paper introduces the pyrazole ring into the C-2 side chain of this derivative,and combines the structural modifications of C-5 and C-6 to construct a series of novel structures.The target molecules of thiomethylpyrazolidine were analyzed and their rationality was analyzed by molecular docking.The synthesis of the target compound is carried out by first synthesizing ?-ketoester by Clay reaction using diethyl malonate as raw material,and then ring-closing reaction with thiourea under base catalysis to obtain 6 kinds of 5-alkyl-6-aryl-2-thiopyrimidine key intermediate.In addition,the methyl ketone compound is used as a raw material,and reacted with diethyl oxalate in a sodium alkoxide solution to form a ketoester,and then heated and condensed with hydrazine hydrate to obtain an ethoxycarbonylpyrazole compound,followed by NCS chlorination,LiAIH4 Reduction,PBr3 bromination or the like gives 8 kinds of 5-aryl-3-(bromomethyl)pyrazole derivatives.Finally,under the catalytic conditions of K2CO3,the 5-aryl-3-(bromomethyl)pyrazole derivative is alkylated with 5-alkyl-6-aryl-2-thiopyrimidine to obtain 2-thiomethyl group.Pyrazole pyrimidinone derivatives.A total of 32 target compounds were synthesized and characterized by 1H NMR and 13C NMR,HRMS and IR.In vitro anti-HIV activity and toxicity experiments were performed on all target molecules using the clinically used anti-AIDS drugs zidovudine(AZT)and nevirapine(NVP)as control drugs.It was found that among the 32 target compounds,15 samples were less toxic to C8166 cells,and CC50 was greater than 200?M.All target compounds showed some in vitro anti-HIV-1 activity with EC50 values ranging from 0.0462?M to 32.8677 ?M.Among them,compounds 129 and 131 have strong anti-HIV-1 activity in vitro,with average EC50 of 0.0547?M and 0.0508?M,respectively,and therapeutic index(SI)greater than 3000;compounds 112,113,117,123,126,128,130,132 the therapeutic index(SI)is between 1000 and 3000.At the same time,the two compounds 129 and 131 with the best activity were selected,and the inhibitory activity against reverse transcriptase of HIV-1 was evaluated using NVP as a control.The results showed that compounds 129 and 131 had significant inhibitory activity against HIV-1RT.The IC50 value of compound 131 was comparable to that of the control drug NVP,and the target of this compound was determined to be HIV-1 RT.Finally,the three-dimensional quantitative structxure-activity relationships of 322-thiomethylpyrazolopyrimidinones NNRTIs synthesized by the subject are studied,and CoMFA and CoMSIA models with good prediction ability are established,which provide theoretical guidance for one-step structural modification of these compounds.